p-hydroxyisovaleric aciduria and - Europe PMC

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crepitations and rhonchi. Chest x-ray showed a left upper lobe pneumonia. Blood gases in oxygen were. Po2 250 Torr and Pco.2 81 Torr; pH 7-2. Preliminary.
Short reports Archives of Disease in Childhood, 1973, 48, 975.

Child with a defect in leucine metabolism associated with

p-hydroxyisovaleric aciduria and p-methylcrotonylglycinuria Three inborn errors of the leucine degradation pathway are known, maple syrup urine disease, isovaleric acidaemia, and ,B-methylcrotonylglycinuria. The latter was first described by Eldjarn and his colleagues in 1970 (Eldjarn et al., 1970; Stokke et al., 1972). The patient they reported excreted large amounts of fl-methyl3-hydroxyisovaleric acid, crotonylglycine and presumably due to a defective activity of the enzyme ,B-methylcrotonyl CoA carboxylase. A second child with these metabolites in his urine was described the following year (Gompertz et al., 1971). The clinical presentations of these two children were entirely different. The first suffered from a neurological condition similar to WerdnigHoffmann disease, while the second presented with vomiting and an acute metabolic acidosis and ketosis. In this report we describe a 9-month-old infant who was admitted moribund with an upper lobe pneumonia and was subsequently shown to be excreting these abnormal metabolites.

He was treated with penicillin, kanamycin, and hydrocortisone. Though blood gases retumed to normal within 12 hours, his state of consciousness remained poor. Since lobar pneumonia alone seemed an inadequate explanation, screening tests for metabolic disease and poisoning were undertaken with these results. Urinary ketones, amino acids, and coproporphyrins, and blood lead and barbiturate levels were all normal. Careful inquiries of the parents showed no access to other poisons, in particular opiates. However, screening for urinary organic acids showed abnormal amounts of ,B-hydroxyisovaleric acid and fl-methylcrotonic acid present. Treatment with biotin (5 mg twice daily orally) was then begun. His clinical state gradually improved over the next 4 days and his level of consciousness, which had fluctuated throughout this period, returned to normal. Assessment 4 weeks after admission showed no localizing neurological signs, though there was some pallor of both optic discs. He was, however, obviously developmentally retarded.

Biochemical studies Urine samples collected on the first 3 days of admission were screened for organic acids using gas chromatographic procedures (Gompertz and Draffan, 1972a). Volatile fatty acids were analysed on a neopentylglycol adipate-phosphoric acid column. Other organic acids and glycine-conjugates were analysed as their methylated derivatives on a polyester column. All three urine samples contained f-hydroxyisovaleric acid, 13-methylcrotonic acid, and /3-methylcrotonylglycine in abnormal Case report amounts. The identity of /3-hydroxyisovaleric acid and A 9-month-old child of first-cousin Pakistani parents ,B-methylcrotonylglycine was confirmed by mass spectrometry (Gompertz and Draffan, 1972b). was admitted with a history of severe respiratory The presence of these three metabolites suggested an difficulty for 6 hours. 2 days before admission he was noted to be lethargic and febrile, and he was prescribed impaired /-methylcrotonyl CoA carboxylase activity. aspirin and penicillin. On admission he appeared This enzyme is biotin dependent and the previous child moribund, with constricted pupils. Temperature 39 'C. reported by us (Gompertz et al., 1971) responded to Respiratory rate was only 12/min, heart rate 100/min. massive doses of biotin. A further urine sample was He was not cyanosed. There was slight intercostal collected, following which biotin 5 mg twice daily was recession and on auscultation there were widespread given orally. Quantitation of the three metabolites was crepitations and rhonchi. Chest x-ray showed a left then performed (Fig. 1). Before biotin administration was granted, the concentration of 1-hydroxyisovaleric upper lobe pneumonia. Blood gases in oxygen were Po2 250 Torr and Pco.2 81 Torr; pH 7-2. Preliminary acid in the urine had fallen from 5-5 mmol/l. to 0 5 investigations included Hb, white cell count, CSF, urea, mmol/l., and there was improvement in the child's clinical status. From the ninth day onwards the trace electrolytes, and blood sugar, and all were normal. At and following birth he had been normal. One amounts of /-hydroxyisovaleric acid and fl-methylmonth before admission he had been seen because of crotonic acid in the urine were within the normal range. Ten days after stopping biotin therapy, the patient was recurrent upper respiratory tract infections, and a delay in motor development was noted. There had been one given 100 mg L-leucine/kg body weight. Timed urine female sib; she had congenital heart disease and died at samples during the next 24 hours were collected. The sample collected between 2 and 4 hours after the loading 10 months, the cause of death not known. 975

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remained well. On his return he was found to be excreting abnormal amounts of f-methylcrotonic (O- 10 - 24 mmol/l.) and ,B-hydroxyisovaleric acids (1 * 1 mmol/l.). Treatment with biotin 10 mg twice daily orally brought the excretion of these metabolites back to normal levels within 48 hours.

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FIG. 1.-Urinary concentrations of ,B-hydlroxyisovaleric acid (PHOIVA), ,B-methylcrotonic acid (flMCA), and

fi-methylcrotonylglycine (fMCG

test contained increased concentrations oif P-hydroxyisovaleric acid and 1-methylcrotonic al absolute terms (Fig. 1) and in relation to from excretion (Fig. 2). Similar results were o another loading test performed one week l;ater.

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